The use of intravitreally placed pharmaceutical agents that inhibit vascular endothelial growth factor (VEGF) is currently the most common form of treatment for neovascular age-related macular degeneration (AMD) and for macular edema secondary to central and branch retinal vein occlusion. Bevacizumab (Avastin®, Genentech) is widely used on an off-label basis in the treatment of neovascular AMD. In addition, ranibizumab (Lucentis®, Genentech) has recently been approved by the US Food and Drug Administration for the treatment of macular edema secondary to central and branch retinal vein occlusion. Both ranibizumab and bevacizumab are widely used off-label for the treatment of diabetic macular edema in the United States. In clinical practice they are injected intravitreally at a frequency no sooner than every 4 weeks for ranibizumab and every 4 to 6 weeks for bevacizumab. Aflibercept (Eylea®, Regeneron) is the newest FDA-approved anti-VEGF agent used for the treatment of exudative AMD. In clinical regimens, aflibercept is typically used for treatment every 4 to 8 weeks.
Intravitreal injection of anti-VEGF agents is the most commonly performed procedure in the treatment of the retina. Systemic side effects have been described with the use of both agents. Ranibizumab has been associated with an increased risk for nonocular hemorrhages (ecchymoses, gastrointestinal hemorrhages, hematoma, vaginal hemorrhages, subdural hematomas), most notably stroke (Rosenfeld P J, et al. N Engl J Med. 2006 355:1419-1431; Brown D M, et al. N Engl J Med. 2006 355:1432-1444). It may be that the treated population is at increased risk for stroke and that patients with a history of stroke appear to be more susceptible (Boyer D S, et al. Ophthalmology. 2009 116:1731-1739; Ueta T, et al. Ophthalmology. 2010 117:1860; Tolentino M. Surv Ophthalmol. 2011 56:95-113). Although the systemic use of bevacizumab has been associated with multiple systemic side effects, including hypertension, proteinuria, wound healing complications, GI perforation, nonocular hemorrhages, and thromboembolic events, these effects have not been systematically studied with intravitreal use and await validation in upcoming clinical trials (Yang J C, et al. N Engl J Med. 2003 359:427-434; Shah M A, et al. J Clin Oncol. 2005 23:2574-2576; Lordick F, et al. Int J Radiat Oncol Biol Phys. 2006 64:1295-1298; Gordon C R, et al. Ann Plast Surg. 2009 62:707-709).
A clinical question that often arises is whether anti-VEGF agents actually remain within the vitreous cavity after intravitreal placement. It remains uncertain whether significant escape occurs from the vitreous cavity into the systemic circulation or into the central nervous system through the optic nerve that may account for systemic side effects. Furthermore, it is unclear whether these agents actually remain in the vitreous cavity for the duration of the 4- to 6-week treatment interval. In addition, the clinical question often arises whether or not the clearance rate of intravitreally placed anti-VEGF agents is more rapid if the treated eye has undergone previous lens or vitreous removal.
Previous pharmacokinetic studies on animal models to determine the intravitreal duration and half-lives of these agents have relied primarily on serial immunoassay measurements from different animals at different time intervals after intravitreal injection rather than serial measurements over time from the same animals (Bakri S J, et al. Ophthalmology. 2007 114:855-859; Bakri S J, et al. Ophthalmology. 2007 114:2179-2182; Kim H, et al. Exp Eye Res. 2006 82:760-762; Gaudreault J, et al. Invest Ophthalmol Vis Sci. 2005 46:726-733). Improved methods for performing pharmacokinetic studies on intravitreally administered agents are needed.